Irene M. Lang

Fibrinolysis for patients with intermediate-risk pulmonary embolism

BACKGROUND The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. METHODS In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. RESULTS Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42). CONCLUSIONS In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. (Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743.).

Bosentan for Treatment of Inoperable Chronic Thromboembolic Pulmonary Hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a Randomized, Placebo-Controlled Trial

OBJECTIVES Our goal was to investigate the effect of treatment with the oral dual endothelin receptor antagonist bosentan on the hemodynamics and exercise capacity of patients with chronic thromboembolic pulmonary hypertension (CTEPH). BACKGROUND CTEPH is characterized by vascular obstruction and remodeling, leading to increased pulmonary vascular resistance (PVR). Although pulmonary endarterectomy (PEA) is potentially curative, medical therapy is needed in patients with inoperable disease or persistent/recurrent pulmonary hypertension after PEA. METHODS The BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension) study was a double-blind, randomized, placebo-controlled study in CTEPH including patients with either inoperable CTEPH or persistent/recurrent pulmonary hypertension after PEA (>6 months after PEA). Independent coprimary end points were change in PVR as a percentage of baseline and change from baseline in 6-min walk distance after 16 weeks of treatment with bosentan or placebo. Secondary end points included change from baseline in World Health Organization functional class and other hemodynamic parameters. RESULTS One hundred fifty-seven patients were enrolled and randomized: 80 to placebo, 77 to bosentan. A statistically significant treatment effect (TE) of bosentan over placebo on PVR was demonstrated: -24.1% of baseline (95% confidence interval [CI]: -31.5% to -16.0%; p < 0.0001). Total pulmonary resistance (TE: -193 dynxsxcm(-5); 95% CI: -283 to -104 dyn.s.cm(-5); p < 0.0001) and cardiac index (TE: 0.3 lxmin(-1)xm(-2); 95% CI: 0.14 to 0.46 lxmin(-1)xm(-2); p = 0.0007) improved. Mean TE on 6-min walk distance was +2.2 m (95% CI: -22.5 to 26.8 m; p = 0.5449). Bosentan treatment was well tolerated. CONCLUSIONS This study demonstrated a positive TE of bosentan on hemodynamics in this patient population. No improvement was observed in exercise capacity. Further trials are needed to define the role of medical therapy in patients with CTEPH (Bosentan Effects in Inoperable Forms of Chronic Thromboembolic Pulmonary Hypertension; NCT00313222).

Mechanisms Underlying Aortic Dilatation in Congenital Aortic Valve Malformation

BACKGROUND The high incidence of aortic disease in subjects with congenital aortic valve malformations suggests a causative relationship between these 2 conditions. The histological observation in aortic dilatation/aneurysm/dissection is Erdheim cystic medial necrosis (CMN), a noninflammatory loss of smooth muscle cells (SMCs), fragmentation of elastic fibers, and mucoid degeneration. METHODS AND RESULTS To examine whether apoptosis is 1 of the mechanisms underlying CMN and aortic medial layer SMC loss, ascending aortic wall specimens from 32 patients were collected at cardiothoracic surgery and examined by histochemical staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling. From echocardiography results, 4 groups of patients were identified: bicuspid valve carriers with (bi/dil) or without (bi/0) aortic dilatation and tricuspid valve carriers with (tri/dil) or without (tri/0) aortic dilatation. Massive focal apoptosis was observed in the medial layers of bi/dil (mean apoptotic index [mAI], 8.1+/-6.0) and tri/dil (mAI, 8.1+/-8.3) compared with tri/0 (mAI, 0.9+/-1.2; P=0.0079 and P=0.037). In bi/0 (mAI, 9.1+/-5.7) compared with tri/0 (mAI, 0.9+/-1.2), rates of medial SMC apoptosis were increased (P=0.0025). Bi/dil (mean age, 40. 6+/-15.7 years) were significantly younger than tri/dil (mean age, 56.4+/-12.8 years) undergoing the same operation (P=0.0123). CONCLUSIONS Premature medial layer SMC apoptosis could be part of a genetic program underlying aortic disease in patients with aortic valve malformations.

Selexipag for the treatment of pulmonary arterial hypertension

BACKGROUND In a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension. METHODS In this event-driven, phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 μg twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo). RESULTS A primary end-point event occurred in 397 patients--41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of the events. The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of two therapies). By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause. Overall, 7.1% of patients in the placebo group and 14.3% of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events. The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain. CONCLUSIONS Among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower with selexipag than with placebo. There was no significant difference in mortality between the two study groups. (Funded by Actelion Pharmaceuticals; GRIPHON ClinicalTrials.gov number, NCT01106014.).

Diastolic Pulmonary Vascular Pressure Gradient: A Predictor of Prognosis in “Out-of-Proportion” Pulmonary Hypertension

BACKGROUND Left-sided heart disease (LHD) is the most common cause of pulmonary hypertension (PH). In patients with LHD, elevated left atrial pressure causes a passive increase in pulmonary vascular pressure by hydrostatic transmission. In some patients, an active component caused by pulmonary arterial vasoconstriction and/or vascular remodeling superimposed on left-sided pressure elevation is observed. This “reactive” or “out-of-proportion” PH, defined as PH due to LHD with a transpulmonary gradient (TPG) > 12 mm Hg, confers a worse prognosis. However, TPG is sensitive to changes in cardiac output and left atrial pressure. Therefore, we tested the prognostic value of diastolic pulmonary vascular pressure gradient (DPG) (ie, the difference between invasive diastolic pulmonary artery pressure and mean pulmonary capillary wedge pressure) to better prognosticate death in “out-of-proportion” PH. METHODS A large database of consecutive cases was analyzed. One thousand ninety-four of 2,351 complete data sets were from patients with PH due to LHD. For proof of concept, available lung histologies were reviewed. RESULTS In patients with postcapillary PH and a TPG > 12 mm Hg, a worse median survival (78 months) was associated with a DPG ≥ 7 mm Hg compared with a DPG < 7 mm Hg (101 months, P = .010). Elevated DPG was associated with more advanced pulmonary vascular remodeling. CONCLUSIONS DPG identifies patients with “out-of-proportion” PH who have significant pulmonary vascular disease and increased mortality. We propose a diagnostic algorithm, using pulmonary capillary wedge pressure, TPG, and DPG in sequence to diagnose pulmonary vascular disease superimposed on left-sided pressure elevation.

Predictors of Outcome in Chronic Thromboembolic Pulmonary Hypertension

Background— Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by intraluminal thrombus organization and fibrous obliteration of pulmonary arteries. Recently, associated medical conditions such as splenectomy, ventriculoatrial shunt for the treatment of hydrocephalus, permanent central intravenous lines, inflammatory bowel disease, and osteomyelitis were found to be associated with the development of CTEPH. The study aim was to define the impact of these novel risk factors on survival. Methods and Results— Between January 1992 and December 2006, 181 patients diagnosed with CTEPH were tracked with the use of our centers customized computer database. A Cox regression model was used to examine relations between survival and associated medical conditions, age, sex, hemodynamic parameters, modified New York Heart Association functional class at diagnosis, CTEPH type, pulmonary endarterectomy, and anti-cardiolipin antibodies/lupus anticoagulant. During a median observation time of 22.1 (range, 0.03 to 152) months, the clinical end point of cardiovascular death or lung transplantation occurred in 48 cases (27%). Pulmonary endarterectomy (hazard ratio, 0.14; 95% CI, 0.05 to 0.41; P=0.0003), associated medical conditions (hazard ratio, 3.17; 95% CI, 1.70 to 5.92; P=0.0003), and pulmonary vascular resistance (hazard ratio, 1.02; 95% CI, 1.00 to 1.04; P=0.04) were predictors of survival. Thirty-day postoperative mortality (24% versus 9%) and the incidence of postoperative pulmonary hypertension (92% versus 20%) were substantially higher in patients with associated medical conditions. Conclusions— CTEPH-predisposing medical conditions, such as splenectomy, permanent central intravenous lines, and certain inflammatory disorders, predict poor survival in CTEPH.

Interventional and surgical modalities of treatment in pulmonary hypertension.

Most patients with chronic thromboembolic pulmonary hypertension are operable, and pulmonary endarterectomy is the treatment of choice. Pulmonary endarterectomy should not be delayed for medical therapy, and risk stratification helps to define patients likely to achieve the best outcome. Inoperable patients should be referred for trials of medical agents. Atrial septostomy is promising but underutilized, although better ways of ensuring an adequate, lasting septostomy still need to be determined. Indications for the procedure are unchanged, and it should be considered more frequently. Bilateral sequential lung or heart-lung transplantation is an important option for selected patients, and potential candidates who are class IV or III but not improving should be referred early to a transplantation center. Currently, there is a need for right ventricular assist devices with flow characteristics suited to the circulation of patients with pulmonary arterial hypertension. Right ventricular synchronization therapy has not yet been tested. Novel shunts (e.g., Potts anastomosis) also hold promise. All surgery for pulmonary hypertension should be performed in centers with experience in these techniques.

Original ResearchPulmonary Vascular DiseaseDiastolic Pulmonary Vascular Pressure Gradient: A Predictor of Prognosis in “Out-of-Proportion” Pulmonary Hypertension

BACKGROUND Left-sided heart disease (LHD) is the most common cause of pulmonary hypertension (PH). In patients with LHD, elevated left atrial pressure causes a passive increase in pulmonary vascular pressure by hydrostatic transmission. In some patients, an active component caused by pulmonary arterial vasoconstriction and/or vascular remodeling superimposed on left-sided pressure elevation is observed. This “reactive” or “out-of-proportion” PH, defined as PH due to LHD with a transpulmonary gradient (TPG) > 12 mm Hg, confers a worse prognosis. However, TPG is sensitive to changes in cardiac output and left atrial pressure. Therefore, we tested the prognostic value of diastolic pulmonary vascular pressure gradient (DPG) (ie, the difference between invasive diastolic pulmonary artery pressure and mean pulmonary capillary wedge pressure) to better prognosticate death in “out-of-proportion” PH. METHODS A large database of consecutive cases was analyzed. One thousand ninety-four of 2,351 complete data sets were from patients with PH due to LHD. For proof of concept, available lung histologies were reviewed. RESULTS In patients with postcapillary PH and a TPG > 12 mm Hg, a worse median survival (78 months) was associated with a DPG ≥ 7 mm Hg compared with a DPG < 7 mm Hg (101 months, P = .010). Elevated DPG was associated with more advanced pulmonary vascular remodeling. CONCLUSIONS DPG identifies patients with “out-of-proportion” PH who have significant pulmonary vascular disease and increased mortality. We propose a diagnostic algorithm, using pulmonary capillary wedge pressure, TPG, and DPG in sequence to diagnose pulmonary vascular disease superimposed on left-sided pressure elevation.

Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding

All available evidence today indicates that chronic thromboembolic pulmonary hypertension (CTEPH) is primarily caused by venous thromboembolism, as opposed to primary pulmonary vascular in situ thrombosis. Both the initial magnitude of clot and pulmonary embolism (PE) recurrence may contribute to the development of CTEPH. Only few specific thrombophilic factors, such as phospholipid antibodies, lupus anticoagulant and elevated factor VIII, are statistically associated with CTEPH. A mechanistic view of CTEPH as a disease caused by obliteration of central pulmonary arteries by pulmonary emboli is too simplistic. Based on available data one may speculate that PE may be followed by a pulmonary vascular remodelling process modified by infection, immune phenomena, inflammation, circulating and vascular-resident progenitor cells, thyroid hormone replacement or malignancy. Both plasmatic factors (hypercoagulation, “sticky” red blood cells, high platelet counts and uncleavable fibrinogens) and a misguided vascular remodelling process contribute to major vessel and small vessel obliteration. Endothelial dysfunction and endothelial–mesenchymal transition may be important, but their precise roles remain obscure. There exists no animal model for CTEPH; therefore, experimentation in the future must include human tissues and clinical data in parallel.

High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is an enigmatic disorder lacking signs, symptoms and classical risk factors for venous thromboembolism. The objective of the prospective case controlled study, carried out at the Pulmonary Hypertension Unit, University Hospital Vienna, Austria, was to investigate whether plasma FVIII is elevated in CTEPH patients. The study examined 122 consecutive patients diagnosed with CTEPH. Plasma FVIII was measured and compared with plasma FVIII of healthy controls (n = 82) and of patients with nonthromboembolic pulmonary arterial hypertension (PAH, n = 88). Results show that CTEPH patients had higher FVIII levels than controls (233 +/- 83IU/dl versus 123 +/- 40IU/dl, p < 0.0001) and PAH patients (158 +/- 61IU/dl, p < 0.0001). Plasma FVIII one year after surgery (212 +/- 94IU/dl) was statistically unchanged compared with preoperative values (FVIII: 226 +/- 88IU/dl, n = 25). FVIII > 230IU/dl was more prevalent in CTEPH patients (41%) than in controls (5%, p < 0.0001) and PAH patients (22%, p = 0.022). We can conclude that elevated plasma FVIII is the first prothrombotic factor identified in a large proportion of CTEPH patients.